12804
J. Am. Chem. Soc. 1996, 118, 12804-12811
Structure and Dynamic Behavior of Crowded Cis Vicinal [(N,N-Dimethylamino)cyclopentyl]trimethylammonium Salts and Related Compounds Gideon Fraenkel,* Sharon Boyd, Albert Chow, and Judith Gallucci Contribution from the Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210 ReceiVed July 8, 1996X
Abstract: Carbon-13 NMR spectra of [cis-2-(N,N-dimethylamino)cyclopentyl]trimethylammonium iodide (4a) and triflate (4b) in acetone-d6 and in CD3NO2 show inversion of the amine with rotation about the ring-N bond to be unusually slow with ∆Hq and ∆Sq (4b in acetone-d6) of 17 kcal/mol and 14 eu, similar to the values for cis-2-tertbutyl-1-(N,N-dimethylamino)cyclopentane (3) in Et2O-d10 of 16 kcal/mol and 17 eu, indicating that steric and not electrostatic interactions are responsible for the slow rates. In addition, the N+ methyls of 4a and 4b, which are magnetically nonequivalent by 13C NMR at low temperatures, undergo signal averaging with increasing temperature, the result of rotation dynamics around the ring-N+ bonds giving for 4b in acetone-d6 ∆Hq and ∆Sq, respectively, of 7.2 kcal/mol and -9 eu. Similar values are found for tert-butyl rotation in 3 in Et2O-d10. Around room temperature for 4a and 4b, 1J(14N,13C) is resolved and found to be ca. 3.6 Hz. With decreasing temperature, this coupling is averaged by progressively faster 14N electric quadrupole induced relaxation. Line shape analysis of the 13C NMR spectra shows Ea for the correlation time to be 2-2.7 kcal/mol. X-ray crystallography of 4b and (cis-2-tertbutylcyclopentyl)trimethylammonium triflate (7) shows the rings to adopt the half-chair structure with vicinal substituents located at the puckered carbons. In 4b, the N+Me3 group is pseudoequatorial with the NMe2 group pseudoaxial; whereas, in 7, the tert-butyl group is pseudoequatorial with the N+Me3 group pseudoaxial. Interesting correlations are noted of 13C NMR shifts of individual methyls with their crystallographic structural assignments.
Cyclic cis vicinal diamines,1 a hitherto neglected class of compounds due to the absence of an efficient preparation, are potentially useful as ligands for metal ions, are catalysts in the formation and reactions of organometallic compounds,2 and show significant physiological activity. The Pt(II) complex of cis-1,2-diaminocyclohexane is an active anticancer agent.3 Several substituted cis vicinal diaminocyclohexanes, for example (()-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, were reported to bind to the σ receptor in the guinea pig brain.4 Our synthesis of cyclic cis vicinal tertiary diamines5a,b rendered these compounds readily accessible for the detailed study of their acid/base behavior and of their dynamics of X Abstract published in AdVance ACS Abstracts, December 1, 1996. (1) (a) Confalone, P. N.; Pizzolato, G.; Uskokovic, M. R. J. Org. Chem. 1977, 42, 135-39. (b) Baker, B. R.; Anerry, M. V.; Safir, S. R.; Bernstein, S. J. Org. Chem. 1946, 12, 138-54. (c) Olsen, R. K.; Hennen, W. J.; Wardle, R. B. J. Org. Chem. 1982, 47, 4605-4611. (d) Parry, R. J.; Kunitani, M. G.; Vielle, O., III J. Chem. Soc., Chem. Commun. 1975, 321. (e) Swift, G.; Swern, D. J. Org. Chem. 1967, 32, 511-517. (f) Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar, D.; Uskokovic, M. R. J. Am. Chem. Soc. 1975, 97, 5936. (g) Mercuriamination: Barluenga, J.; AlonsoCives, L.; Ansenio, G. Synthesis 1979, 962-964. (h) Barluenga, J.; Aznar, F.; Liz, R. J. Chem. Soc., Chem. Commun. 1981, 1181-1182. (i) Aminopalladation: Ba¨ckvall, J. Tetrahedron Lett. 1978, 163-166. (j) Chong, A. O.; Oshima, K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 3420-3426. (k) Sharpless, K. B.; Singer, S. P. J. Org. Chem. 1976, 41, 2504-2506. (l) Levy, N.; Scaife, W.; Wilder-Smith, A. E. J. Chem. Soc. 1948, 52-60. (m) Marx, M.; Marti, F.; Reisdorff, J.; Sandmeier, R.; Clark, S. J. Am. Chem. Soc. 1977, 99, 6754. (n) Broadbent, H. S.; Allred, E. L.; Pendleton, L.; Whittle, W. C. J. J. Am. Chem. Soc. 1960, 82, 189-93. (o) Becker, P. N.; White, M. A.; Bergman, R. G. J. Am. Chem. Soc. 1980, 102, 5676. (p) Kohn, H.; Jung, S. H. J. Am. Chem. Soc. 1983, 105, 4106. Jung, S. H.; Kohn, H. J. Am. Chem. Soc. 1985, 107, 2931. (q) Heine, H. G.; Fischler, H. M. Chem. Ber. 1972, 105, 975. (2) For example, see: Langer, H. W. Polyamine Chelated Alkali Metal Compounds; Advances in Chemistry Series 130; American Chemical Society: Washington, DC, 1974; p 1. (3) Gill, D. S.; Rosenberg, B. J. Am. Chem. Soc. 1982, 104, 4598.
S0002-7863(96)02327-X CCC: $12.00
conformational interconversion.6 In the course of this work, we had occasion to prepare and investigate quaternary ammonium derivatives of these compounds. They displayed unusual dynamic behavior. This paper reports X-ray crystallographic studies and NMR investigations of dynamics in what now appear to be unusually crowded molecular species. Results and Discussion For convenience, the amines used in this work are listed as 1 to 3 together with their corresponding quaternary ammonium salts, 4-7.
Of the compounds used in this work, cis-1,2-di(N,N-dimethylamino)cyclopentane (1) was prepared as described previously.5,6 In parallel fashion, cis-2-tert-butyl-1-(N,N-dimethyl(4) (a) DeCosta, B. R.; Redesca, L. Heterocycles 1990, 31, 1837. (b) DeCosta, B. R.; Bowen, W. D.; Hellewell, S. D.; George, C.; Rothman, R. B.; Reid, A. A.; Walker, J. M.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 1989, 32, 1996-2002.
© 1996 American Chemical Society
Structure and Dynamic BehaVior
J. Am. Chem. Soc., Vol. 118, No. 50, 1996 12805
Table 1. Quaternization of Amines
A 1 1 2 2 4a 3
N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)2
B N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)3+IC(CH3)3
reagent, solvent cis cis trans trans cis cis
CH3I, Et2O CF3SO3CH3, CH2Cl2 CH3I, Et2O CF3SO3CH3, CH2Cl2 picric acid, Et2O CF3SO3CH3, CH2Cl2
C + I
N(CH3)3 N(CH3)3+CF3SO3N(CH3)3+IN(CH3)3+CF3SO3N(CH3)2 N(CH3)3+CF3SO3-
D N(CH3)2 N(CH3)2 N(CH3)2 N(CH3)3+CF3SO3N(CH3)3+ picrateC(CH3)3
cis cis trans trans cis cis
4a 4b 5a 6 4c 7
amino)cyclopentane (3) came from hydrogenation over Pd(C) of the enamine 9 obtained from 2-tert-butylcyclopentanone7 (8).
Compound 3 was assigned the cis structure on the basis that cyclic aminoenamines were already known to undergo catalytic hydrogenation on the unhindered side.5 Subsequent X-ray crystallography of quaternary ammonium salt 7 confirmed the assignment (see below). trans-Diamine 2 was prepared by sodium in hot ethanol reduction of the anti-dioxine of cyclopentane-1,2-dione8 followed by Eschweiler-Clark reductive alkylation of the resulting trans-1,2-diaminocyclopentane (10).
Formation of quaternary ammonium salts is summarized in Table 1. Alkylation of cis-diamine 1 using CH3I, methyl triflate, or methyl picrate gave only monoquaternization (compound 4). Repulsion between cis, N+ substituents must render the corresponding transition state energetically inaccessible. However, with the nitrogens further apart, the trans-diammonium ditriflate 6 is rapidly formed and is stable. Amines 1 and 3 were monoalkylated with methyl triflate as indicated in Table 1, and the resulting quaternary ammonium triflates 4b and 7 were subjected to X-ray crystallography. The salient feature of these two structures is that the cyclopentane ring adopts the half-chair configuration with the vicinal substituents located on the puckered carbons (Figure 1 and 2). In 4b, the trimethylammonium substituent is pseudoequatorial with the dimethylamino substituent pseudoaxial. Compound 7 has a similar arrangement with the tert-butyl pseudoequatorial and the trimethylammonium pseudoaxial. This is clearly seen by reference to the appropriate torsion angles (Table 2). The tertbutyl group of 7 and the trimethyl ammonium group of 4b have torsion angles within the range of ((165-180)° with respect to the unsubstituted ring carbons, whereas the corresponding values for the dimethylamine in 4b and the trimethylammonium in 7 are 97.4(4)° and -99.0(6)°, respectively. (5) (a) Fraenkel, G.; Gallucci, J.; Rosenzweig, H. S. J. Org. Chem. 1989, 54, 677-681. (b) Previous procedures are summarized in cited refs 3-13 in ref 5a (given here). (c) Fraenkel, G.; Pramanik, P. J. Org. Chem. 1984, 49, 1314. (6) Fraenkel, G.; Balasubramanian, V.; Chang, H. L.; Gallucci, J. J. Am. Chem. Soc. 1993, 115, 6795-6802. (7) Chan, J. H.; Paterson, J.; Pinnsonnault, J. Tetrahedron Lett. 1977, 48, 4183. (8) (a) Jaeger, F. M.; Blumendal, H. B. Z. Anorg. Chem. 1928, 161. (b) Belcher, R.; Hoyle, W.; West, T. S. J. Chem. Soc. 1961, 667. (c) Toftland, H.; Pederson, E. Acta Chem. Scand. 1972, 26, 4019.
Figure 1. ORTEP drawing of 4b. The non-hydrogen atoms are represented by 50% probability thermal ellipsoids. The hydrogen atoms are drawn with an artificial radius.
Figure 2. ORTEP drawing of 7. The non-hydrogen atoms are represented by 50% probability thermal ellipsoids. The hydrogen atoms are drawn with an artificial radius.
Within the pseudoequatorial substituents, N+(CH3)3 in 4b and tert-butyl in 7, one methyl group is sited perpendicular to the cyclopentane plane and the other two point away from the ring. This reduces hydrogen-hydrogen interactions. The bond to the pseudoaxial substituent nearly parallels the bond connecting the vertical methyl to the pseudoequatorial substituent. The crystal structure of 4b is also consistent with 13C NMR data for 4b in acetone-d6. At low temperature, rotation around the ring-N+ bond is slow enough to resolve three lines for the nonequivalent N+ methyls (see below). One is unusually shielded with respect to the other two by 6-7 ppm and thus correlates with the perpendicular ammonium methyl seen with X-ray crystallography. The structure of 4b is similar to that of the monopicrate of cis-1,2-bis(dimethylamino)cyclopentane. X-ray crystallography showed the protonated nitrogen to be pseudoequatorial; the methyls point away from the ring with the NH+ proton and picrate hydrogen-bonded to it, perpendicular to the three methylene carbon plane.6 Bond lengths and distances between groups indicate that the ring in 7 is larger and less symmetrical than that of 4b. The average ring bond length in 4b is 1.52 Å with a range of 1.5881.511 Å, and in 7 it is 1.54 Å with a range of 1.588-1.527 Å.
12806 J. Am. Chem. Soc., Vol. 118, No. 50, 1996
Fraenkel et al.
Table 2. Selected Crystallographic Structural Parameters 4a C(1) C(1) C(2) C(3) C(4) N(1) N(2) C(1) C(2) C(2) C(3) C(1) N(1) N(2)
C(2) C(5) C(3) C(4) C(5) C(1) C(2) C(2) C(3) C(1) C(4) C(5) C(1) C(2)
C(3) C(4) C(5) C(5) C(4) C(2) C(1)
7 Bond Length (Å) 1.528(5) C(1) 1.511(6) C(1) 1.528(6) C(2) 1.508(6) C(3) 1.523(6) C(4) 1.528(4) N 1.457(5) C(2) Bond Angles (deg) 100.6(3) C(1) 100.0(4) C(2) 100.9(3) C(2) 107.2(4) C(3) 103.6(4) C(1) 118.5(3) N 117.0(3) C(1)
C(2) C(5) C(3) C(4) C(5) C(1) C(6) C(2) C(3) C(1) C(4) C(5) C(1) C(2)
1.588(7) 1.533(8) 1.527(8) 1.528(9) 1.548(10) 1.544(7) 1.557(7) C(3) C(4) C(5) C(5) C(4) C(2) C(6)
104.7(4) 105.7(5) 100.5(4) 106.3(5) 108.5(5) 120.8(4) 127.3(4)
Torsion Angles (deg) N(1) C(1) C(2) N(2) 44.3 N C(1) C(2) C(6) -59.4(7) N(2) C(2) C(3) C(4) 97.4(4) N C(1) C(5) C(4) -99.0(6) N(1) C(1) C(5) C(4) 107.1(3) C(4) C(3) C(2) C(6) -179.4(5)
In the separation of the groups, the C1-C2 bond of 7 is 1.588(7) Å and that of 4b is 1.528(8) Å. The length of the N1-C1 bond is 1.544(7) Å for 7 and 1.528(4) Å for 4b. The C2-C6 bond is 1.557(7) Å, and the N2-C2 bond of 4b is 1.457(5) Å. The distance between N1 and C6 of 7 is 3.558(7) Å, and the distance between N1 and N2 of 4b is 3.085(5) Å. The bond angles in Table 2 show the increased distortion of 7 due to the two bulky groups. In 7, the N-C1-C2 angle is 120.8(4)° and the C1-C2-C6 angle is 127.3(4)°. For 4b, the N1-C1-C2 angle is 118.5(3)° and the N2-C2-C1 angle is 117.0(3)°. The bond angles for the cyclopentyl ring are larger (∼2°) for 7 compared to those of 4b. The positioning of the methyl groups is reflected in the bond angles. The Cring-N+CH3 angle in 4b for the methyl sited over the ring is 114° while the other methyls are near the sp3 hybridization angle with values of 108° and 109°. In sum, the X-ray structures show that the cyclopentane rings distort to accommodate adjacent bulky groups. The NMR data for compounds 3 to 7 displayed some unexpected correlations as well as detailed insight into the dynamic behavior of three particular species (4a, 4b, and 3). At room temperature, 13C NMR spectra of N(CH3)2 in 1-5 all show single lines with much the same shifts (see Table 3), apparently independent of electrostatic and steric effects. The series includes cis and trans vicinal diamines as well as cis and trans vicinal aminoammonium salts. In compounds 4a and 4b at low temperature, 13C NMR spectroscopy shows the N(CH3)2 methyls to be magnetically Table 3.
a
1 2a 4ab 4bb,d 5ab 6b,d 3c 7b,d
a
13C
Figure 3. 13C NMR compound 4a in CD3NO2, N(CH3)2 part (left) observed at different temperatures and (right) calculated to fit with rate constants.
nonequivalent (see Figures 3 and 4), conditions under which the rates of inversion at nitrogen and rotation around the ringN(CH3)2 bonds are slow relative to the NMR time scale. To see whether this behavior was unique to the proximity of a cis vicinal trimethylammonium substituent, the 13C NMR of 3, isoelectronic with the cation moiety of 4b, was also obtained at low temperature (Figure 5). The N(CH3)2 13C NMR resonance of 3 behaved in similar fashion to those of 4a and 4b; hence, the line shape changes are of steric and not electrostatic origin. As seen in Table 4, the 13C NMR shifts within each dimethylamino pair for 3, 4a, and 4b are remarkably similar. One methyl at ca. δ 46 is quite similar to that in a “normal” acyclic environment; the other is shielded by ca. 7 ppm. This suggests that the structure of 3 is similar to that of 4b, with the dimethylamino group being pseudoaxial with the shielded methyl at δ 38-39 directed over the cyclopentane moiety, by analogy to the X-ray crystallographic results. At room temperature all but one of the quaternary ammonium salts display spin coupling between the 14N and the directly bonded 13C of methyl of around 4 Hz (see Table 3), the
NMR Shifts (δ) and 1J(13C,14N) Values (Hz) for Amines and Salts (at 300 K)
cis trans cis cis trans trans cis cis
L
M
1
2
3
4
5
L
M
NMe2 NMe2 NMe3+INMe3+CF3SO2NMe3+INMe3+CF3SO3NMe2 NMe3+CF3SO3-
NMe2 NMe2 NMe2 NMe2 NMe2 NMe3+CF3SO3CMe3 CMe3
68.72 69.97 74.86 74.88 76.82 77.36 67.08 80.23
68.72 69.97 64.24 64.12 66.28 77.36 35.77 56.21
25.91 26.75 20.23 19.95 22.18 29.01 23.07 25.08
22.00 24.32 19.94 19.64 20.34 25.59 22.50 19.98
25.91 26.75 23.52 23.06 26.24 29.01 25.64 26.60
44.32 42.99 53.03 52.14 52.53 52.93 43.56 53.92
44.32 42.99 43.08 43.15 40.99 52.93 28.91 32.03 30.46 32.01
CDCl3 solution. b Acetone-d6. c Diethyl ether-d10. d Triflate 1J(13C,19F) ) 320 Hz.
1J(13C,14N)
3.4 3.4 3.9 3.4
Structure and Dynamic BehaVior
J. Am. Chem. Soc., Vol. 118, No. 50, 1996 12807 Table 4. Low Temperature 13C NMR Chemical Shifts (δ) for cis-1-N(CH3)2-2-X(CH3)3-c-C5H8 X(CH3)3 3a 4aa 4ab 4ba a
X(CH3)3
23.21 47.45
29.6 52.96
33.5 55.99
47.00
52.92
56.05
C(CH3)3 N(CH3)3+IN(CH3)3+IN(CH3)3+CF3SO3-
N(CH3)2 39.64 39.15 39.64 38.19
46.8 46.36 46.79 46.23
Acetone-d6. b Nitromethane-d3.
Figure 4. 13C NMR compound 4b in acetone-d6, N(CH3)2 portion (left) observed at different temperatures and (right) calculated to fit with rate constants.
Figure 6. 13C NMR compound 4a in acetone-d6, N(CH3)3+ part (left) observed at different temperatures and (right) calculated to fit with rate constants for rotation and 14N quadrupole-induced relaxation.
Figure 5. 13C NMR compound 3 in diethyl ether-d10, N(CH3)2 part (left) observed at different temperatures and (right) calculated line shapes, to fit with rate constants.
exception being the trans-1,2-diammonium salt 6. Evidently, electric field gradients around the 14N in these salts must be quite small compared to most ammonium salts wherein 14N electric quadrupole-induced relaxation is fast enough to average 1J(13C,14N). In addition to common values for the latter spin coupling, the 13C NMR shifts for NCH3+ are similar for the ammonium salts. With decreasing temperature, the triplet
structure due to 1J(13C,14N) in 4a and 4b in acetone-d6 solution undergoes averaging, due to faster 14N nuclear electric quadrupole-induced relaxation, followed by extensive broadening of the resonance and then by 200 K three lines of equal intensity resolve indicating that by this temperature rotation around the ring-N+ bond has become slow relative to the NMR time scale (see Figures 6 and 7). The spacing of the three NCH3+ 13C NMR resonances of 4a and 4b at low temperature is quite similar to that seen for the C methyls of cis-2-tert-butyl-1-(N,Ndimethylamino)cyclopentane (3) in Et2O-d10 solution at 170 K (see Table 4). One can also conclude that the N+ methyls in 4a and 4b and the C methyls in 3 must reside in similar environments; in each case, one methyl is shielded with respect to the other two in the group. This is consistent with the crystallographic finding that one of the ammonium methyls of 4b is perpendicular to the three methylene carbon plane of the ring and the other two are pointing away from the ring (Figure 1). The significance of the N+-CH3 13C NMR data will be further discussed below. NMR line shapes for the 13C NMR resonances of the dimethylamino methyls were calculated as a function of the composite rate of inversion at nitrogen with rotation around the ring-N bond.9 This resonance is treated as an uncoupled, equally populated, two half-spin exchanging system (eq 1), wherein the numbers label the spins (13C) and X and Y stand for the two environments.9 Comparison of experimental N(CH3)2 (9) (a) Gutowsky, H. S.; Saika, H. J. J. Chem. Phys. 1953, 21, 1688. (b) Gutowsky, H. S.; Holm, C. H. Ibid. 1957, 25, 1288. (c) Kaplan, J. I.; Fraenkel, G. J. Am. Chem. Soc. 1972, 94, 2907.
12808 J. Am. Chem. Soc., Vol. 118, No. 50, 1996
X1Y2 a Y1X2
Fraenkel et al.
(1)
13C
NMR line shapes for compounds 4a, 4b, and 3 with the calculated line shapes, respectively, (Figures 6-8) provides the rate constants for inversion/rotation treated in, for example, the Eyring plot shown in Figure 9. Table 5 lists the associated activation parameters. The similarity of ∆Hq for 4a and 4b might have been expected; that their values resemble the barrier for 3 confirms the similarity of the N-(CH3)2 environments in all three species as proposed above and implies that the mechanisms for inversion/rotation must be similar and that steric effects are predominantly responsible for the large magnitude of the barriers rather than electrostatic interactions. Ordinarily in the absence of steric effects such barriers are much lower than those found in this work. For example, in N,N-dimethyltert-butylamine the value is 6 kcal/mol.10 Symbols used in the following NMR line shape calculations are conveniently collected in Table 6. Carbon-13 NMR line shape changes for the tert-butyl methyls of 3 due to rotation around the tert-butyl ring bond are treated as an equally populated uncoupled three half-spin exchanging system (eq 2).11 Figure 7.
13C
NMR compound 4b in acetone-d6 as in Figure 6.
(2)
the absorption is given by the summation (eq 3)
Abs(
